Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.139G>C (p.Asp47His)

CA404074850

440546 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 67b39111-3008-4f7c-ad1e-56534ac6aeb8

HGVS expressions

NM_000527.5:c.139G>C

NM_000527.5(LDLR):c.139G>C (p.Asp47His)

NC_000019.10:g.11100294G>C

CM000681.2:g.11100294G>C

NC_000019.9:g.11210970G>C

CM000681.1:g.11210970G>C

NC_000019.8:g.11071970G>C

NG_009060.1:g.15914G>C

ENST00000558518.6:c.139G>C

ENST00000252444.9:n.393G>C

ENST00000455727.6:c.139G>C

ENST00000535915.5:c.139G>C

ENST00000545707.5:c.139G>C

ENST00000557933.5:c.139G>C

ENST00000557958.1:n.225G>C

ENST00000558013.5:c.139G>C

ENST00000558518.5:c.139G>C

ENST00000560502.5:n.225G>C

NM_000527.4:c.139G>C

NM_001195798.1:c.139G>C

NM_001195799.1:c.139G>C

NM_001195800.1:c.139G>C

NM_001195803.1:c.139G>C

NM_001195798.2:c.139G>C

NM_001195799.2:c.139G>C

NM_001195800.2:c.139G>C

NM_001195803.2:c.139G>C

Uncertain Significance

PP3 PM2

PS2 PS4 PS3 PS1 PVS1 PP4 PP1 PP2 BA1 PM6 BS4 BS3 BS1 PM1 PM4 PM3 PM5 BS2 BP7 BP5 BP3 BP2 BP4 BP1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.139G>C (p.Asp47His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755 The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.977. It is above 0.75, so met.

PP3

REVEL = 0.977. It is above 0.75, so met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

PS2

there is no case data available for this variant

PS4

there is no case data available for this variant

PS3

variant was not studied in functional studies, so not met

PS1

no other missense variant leads to the same amino acid change, so not met

PVS1

variant is missense and not in initiation codon, so not applicable

PP4

there is no case data available for this variant

PP1

there is no case data available for this variant

PP2

not applicable

BA1

This variant is absent from gnomAD (gnomAD v2.1.1).

PM6

there is no case data available for this variant

BS4

there is no case data available for this variant

BS3

variant was not studied in functional studies, so not met

BS1

This variant is absent from gnomAD (gnomAD v2.1.1).

PM1

variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so not met

PM4

variant is missense, so not applicable

PM3

there is no case data available for this variant

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.139G>T (p.Asp47Tyr) - VUS by these guidelines - NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) - VUS by expert panel on ClinVar so not met

BS2

there is no case data available for this variant

BP7

variant is missense, so not applicable

BP5

not applicable

BP3

not applicable

BP2

there is no case data available for this variant

BP4

REVEL = 0.977. It is not below 0.50, so not met

BP1

not applicable

Approved on: 2021-12-13

Published on: 2022-07-11

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